The prevalence of peripheral neuropathy among the patients with diabetes in Pakistan: a systematic review and meta-analysis

The most frequent complication of diabetes is peripheral neuropathy. The estimated prevalence of peripheral neuropathy in people with diabetes varies substantially between published studies in Pakistan. We conducted this meta-analysis to summarize the prevalence of peripheral neuropathy in people with diabetes. Different electronic databases were systematically searched using keywords and MeSH terms. Random-effects meta-analysis was conducted to pool the prevalence of peripheral neuropathy in people with diabetes in Pakistan. Heterogeneity was investigated by random-effects meta-regression and stratification. Two independent authors reviewed studies, extracted data, and conducted the risk of bias analysis. Nineteen studies with a total of 8487 diabetic patients were included. The overall pooled prevalence of diabetic peripheral neuropathy was 43.16% (95% CI 32.93–53.69%), with significant heterogeneity between estimates. The prevalence of peripheral neuropathy among those newly diagnosed with diabetes was 26.52% (95% CI 14.97–39.96%, n = 5). According to the subgroup meta-analysis, the pooled prevalence of diabetic peripheral neuropathy was highest in Khyber Pakhtunkhwa (55.29%; 95% CI 23.91–84.50%), followed by Sindh (40.04%; 95% CI 24.00–57.25%), and the lowest was found in Punjab (34.90%; 95% CI 15.05–57.95%). A significant association was found between the pooled prevalence estimate and the duration of diabetes. The results of this meta-analysis indicate a relatively high prevalence of peripheral neuropathy in people with diabetes in Pakistan. The study protocol has been registered in the PROSPERO, with the registration number CRD42022371617.

www.nature.com/scientificreports/ frequently associated with sleep problems, anxiety, and sadness 13 . In the patients with diabetes, peripheral nerve degeneration is typically irreversible 14 . This has prompted healthcare practitioners to prioritize preventing and identifying modifiable risk factors 14 .
The increasing number of cases of diabetes and the problems it causes are becoming a primary concern in Pakistan, affecting the health and well-being of individuals and families [15][16][17][18][19][20] . According to the IDF 2021, Pakistan has the highest prevalence (26.3%) of diabetes globally. It has on 3rd highest number of the patients with diabetes after China (140 million) and India (74 million), with 1 out of 4 adults living with diabetes in the country 21 . Diabetes is the major cause of peripheral neuropathy in Pakistan. Published studies have reported the prevalence of peripheral neuropathy in people with diabetes in Pakistan varies substantially that, ranging from 16.30% 22 to 79.50% 23 . Thus, this study aimed to systematically gather and summarize existing data on the prevalence of peripheral neuropathy among patients with diabetes in Pakistan. To the best of our knowledge, no prior research has attempted to pool the data on the prevalence of diabetic peripheral neuropathy in Pakistan.

Methods
This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines 24 . The protocol for this review has been registered in the PROSPERO International Prospective Registry of Systematic Reviews with the registration number CRD42022371617 (Supplementary Information).
Search strategy. We extensively searched for publications on the prevalence of diabetic peripheral neuropathy in Pakistan, using multiple databases, including Medline via PubMed, Web of Science, Google Scholar, and local Pakistani databases. The search included publications from inception till December 30th, 2022. We combined medical subject terms with search phrases such as "diabetes and peripheral neuropathy", "diabetic peripheral neuropathy", "diabetic neuropathy", "DPN", diabetic complication", "prevalence" and "Pakistan". The last search was conducted on 31 December 2022. Two authors (S.A. and F.H.) independently screened all publications for eligibility, with differences addressed by a third author (S.R.S.).
Inclusion and exclusion criteria. Studies were considered for inclusion in the quantitative synthesis if they fulfilled the criteria outlined: (i) reported the prevalence or provided enough information to calculate it for diabetic peripheral neuropathy; (ii) were based on a hospital, population, or community surveys; and (iii) were written in English. Studies were excluded if they: (i) were not related to peripheral neuropathy in people with diabetes; (ii) were reviews; (iii) were case series or case reports; (iv) were about Pakistani communities outside of Pakistan; (v) had data that was published in more than one study (the most recent version was used); and (vi) did not have full text available.
Risk of bias assessment. Using the Joanna Briggs Institute Critical Appraisal 25 checklist, two authors (F.H. and A.A.) independently assessed the methodological quality of each selected study. Disputes over the quality evaluation checklist were handled by discussion or consulting a third investigator (S.R.S.). Each study was rated as good (scores greater than 69%), medium (scores between 50 and 69%), or poor (scores below 50%). Data extraction. Two independent authors (A.A. and F.H.) obtained the following information from each included study using a standardized form: The following data is abstracted: Surname of the first author, year of publication, prevalence, study design, sample size, setting, geographic location, type of diabetes, sex (male or female), the percentage of male patients, the working year, the mean age of the patients, sampling method, risk of bias, the percentage of diabetes and hypertensive patients, the percentage of the patients who were smokers, the percentage of patients who were obese or overweight, and the prevalence of diabetes in the participants' families. A third author (S.A.) resolved disagreements by discussion and adjudication.
Statistical analysis. Random-effects (DerSimonian and Laird) models were employed because of the assumed heterogeneity between the studies. The statistical analysis was performed through the statistical software R and two packages (meta and metafor). Before combining prevalence estimates, Freeman-Tukey double arcsine transformation 26,27 of percentage was applied to stabilize variances. Furthermore, for all pooled estimates, 95% prediction intervals were computed 27 . A Forest plot was produced to visualize pooled point estimates and their respective confidence interval (CIs). Between-study heterogeneity was quantified through the I 2 index and tested using Cochran Q statistics 28 . Publication bias (small study effect) was visually inspected through a funnel plot and quantitatively tested using the Egger 29 and Begg 30 correlation tests. We further investigated potential sources of statistical heterogeneity employing meta-regression and subgroup meta-analysis. We did not create a multivariable meta-regression model due to the small number of publications. Two-sided P < 0.10 indicated statistical significance. The amount of total between-study variability explained by covariates in the regression models was assessed using the R 2 metric. We performed a leave-one-out sensitivity analysis on meta-analysis to check if any study was highly influential 31 . We determined the level of agreement between raters for the study inclusion and the data extraction using Cohen's kappa coefficient (κ) 32 .

Results
We identified 642 potential articles from the electronic databases and eight additional articles from the reference list of the identified articles. After screening the titles and abstracts, we deleted 323 duplicate publications and excluded 283 entries, as shown in Fig. 1 41 , and three were rated high bias 23,45,47 . It was found that there was an inter-rater agreement of 0.81 for study selection and 0.88 for data extraction between the authors.
Pooled prevalence.  (Fig. 2). High heterogeneity was noted across   www.nature.com/scientificreports/ CI 28.50-80.94%), respectively. Diabetic peripheral neuropathy is more prevalent in people over the 60-80 age group, and the prevalence increases with age. According to univariate meta-regression analysis, only the duration of diabetes of the diabetic patient was statistically significant (β = 0.0211; 95% CI 00.0017-0.0405; P = 0.03, R 2 = 17.20%). There was no statistically significant relationship between prevalence and publication year, smoking, obesity, hypertension, mean age, sample size, methodological quality, or percentage of males in the sample (Table 3).

Discussion
Diabetes is a chronic condition that makes it difficult for a person to control the amount of sugar in their blood. It is a leading cause of many health complications, including diabetic peripheral neuropathy, a type of nerve damage affecting the feet and legs. As a primary objective of this study, we compiled data on the prevalence of diabetic peripheral neuropathy among and their correlated risk factors in Pakistan. It is anticipated that this meta-analysis will help fight against peripheral neuropathy and its complications by supplying information that will assist in public health efforts. The total number of patients with diabetes in the selected studies was 8487. The overall pooled prevalence of peripheral neuropathy in patients with diabetes was 43.16% (95% CI 32.93-53.69%). This finding is in line with a meta-analysis performed in Latin America and the Caribbean (46.5%) 50 , Saudi Arabia (40.2) 51 , and Africa 46% 52 . Our study found a higher prevalence than similar studies conducted in other countries, which found a prevalence of 35.78% 53 worldwide (31%) 54 Ethiopia is 22% 55 . However, the prevalence was lower than that of a similar study performed in Iran, which found a prevalence rate of 53% 56 . It's possible that the discrepancy is due to different diagnostic criteria for diabetic peripheral neuropathy, getting diagnosed early, and starting therapy right away.
In newly diagnosed diabetes patients, the prevalence of peripheral neuropathy was substantially lower than in overall patients. The prevalence rate of peripheral neuropathy was 26.52% among newly diagnosed patients with diabetes. Our results are in line with a recent study (26.1%) conducted on newly diagnosed type-2 diabetes 57 .
Subgroup meta-analysis by study location revealed that the pooled prevalence of peripheral neuropathy in the patients with diabetes was highest in Khyber Pakhtunkhwa (55.29%), followed by Sindh (40.04%) and lowest in Punjab (34.90%). This disparity in the prevalence may be due to socioeconomic and sociocultural differences  www.nature.com/scientificreports/ between populations, variations in screening methods, regional differences, seasonal and climate factors, lifestyle habits, and eating habits. Subgroup meta-analysis by age group revealed that the prevalence of diabetic peripheral neuropathy was significantly higher among the older age patients than among the younger age patients. Diabetic patients aged 60 years and over are twice more likely to have peripheral neuropathy problems than those aged 20-40 years. The findings also showed that the duration of diabetes is one of the significant risk factors for peripheral neuropathy disease. The pooled prevalence of peripheral neuropathy in patients with diabetes with a time duration of more than 5 years (56.77%) is greater than in the patients with less than 5 years of diabetes duration (34.64%). Our results are consistent with earlier studies 58,59 .
Our meta-analysis also showed several limitations. First, we discovered significant heterogeneity between studies, therefore we performed meta-regression and subgroup analysis to identify the sources of heterogeneity and an adjusted analysis to account for the variance caused by different factors. Statistical heterogeneity is commonly reported in meta-analyses of prevalence data 60,61 . Secondly, only one study had a low risk of bias while 15 of the studies had a medium risk of bias and 3 had a high risk. Thirdly, our results are based on data from only three provinces, lacking data from two other provinces, limiting generalization to the entire country. Finally, our study only included peer-reviewed studies and excluded grey literature, which could have resulted in publication bias.
Despite the limitations, this meta-analysis represents the first study of its kind to find a pooled prevalence of diabetic peripheral neuropathy in Pakistan. Our transparent approach involved publishing a study protocol and utilizing scientific and statistical methods, including subgroup and meta-regression analyses, to account for potential influencing variables in our estimate.

Conclusion
The estimated prevalence of peripheral neuropathy in patients with diabetes in Pakistan is around 43%. The condition is more common in those who have poorly controlled diabetes and is a major of morbidity and mortality in the Pakistani population. Early detection and treatment of peripheral neuropathy are critical for preventing the condition's progression and complications.

Data availability
All data are included in this manuscript and presented in Table 1.